Atrial fibrillation is associated with an increased risk of stroke and therefore prevention of stroke has been a central goal of therapy in these patients.¹ Vitamin K antagonists (VKAs) have been the standard for stroke prevention as they have been shown to reduce stroke by 64%.² Despite their efficacy, there are many factors that limit their use including a narrow therapeutic window, multiple drug-drug and food interactions, bleeding risk, and requirement of international normalized ratio (INR) monitoring.³ These disadvantages of VKAs are, at least in part, responsible for underuse of anticoagulation. Novel oral anticoagulants have therefore been developed with more predictable anticoagulation effect that eliminates the need for routine therapeutic monitoring.⁴ Three new agents have been FDA approved for anticoagulation in patients with non-valvular atrial fibrillation: dabigatran, rivaroxaban, and apixaban. In this topic review, we will focus on apixaban and the results of the ARISTOTLE trial (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation).

Apixaban is an oral direct factor Xa inhibitor. It is 75% hepatically metabolized and the rest is renally excreted. Potential drug-drug interactions are with potent CYP3A4 inhibitors. ARISTOTLE was a double-blind, double-dummy randomized trial in which patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke were assigned to treatment with apixaban or dose-adjusted warfarin (target INR 2.0-3.0). Patients receiving apixaban were treated with 5 mg twice daily (2.5mg twice daily in high risk patients defined as having two of the following three criteria; age at least 80 years, weight less than or equal to 60kg, and creatinine greater than or equal to 1.5 mg/dL). The primary efficacy outcome was stroke or systemic embolism and the primary safety outcome was major bleeding. Secondary outcomes included all-cause death and myocardial infarction and a composite of major bleeding and clinically relevant non-major bleeding. The primary outcome occurred in 212 patients (1.27% per year) in the apixaban arm versus 265 patients (1.60% per year) in the warfarin arm (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.95, p<0.0001 for non-inferiority, p= 0.011 for superiority) demonstrating superiority of apixaban over warfarin in the reduction of stroke or systemic embolism. Apixaban was also associated with a 31% relative risk reduction in major bleeding (HR 0.69, 95% CI 0.60-0.80, p < 0.0001) and an 11% relative risk reduction in all-cause mortality (HR 0.89, 95% CI 0.80-0.99, p = 0.047). Intracranial hemorrhage was reduced by 58% (p<0.001), and gastrointestinal bleeding was numerically lower with apixaban (HR 0.89 (95% CI 0.70-1.15, p=0.37).

The benefits of apixaban versus warfarin on reducing stroke and causing less bleeding are consistent across major subgroups in the trial, including in the elderly, in patients with renal insufficiency, with prior stroke, and with higher aggregate risk. Compared to warfarin, apixaban significantly reduced rates of stroke or systemic embolism across varying risk of stroke as defined by CHADS₂ or CHA₂DS₂ VASc scores of 1, 2 or 3 and greater, as well as resulted in lower rates of major bleeding across risk groups defined by either. CHADS₂ or HAS-BLED scores. Patients with prior stroke or TIA are at high risk of subsequent stroke, and this population had similar relative and greater absolute reduction in stroke or systemic embolism with apixaban.⁵

Patients with reduced renal function have higher rates of stroke, systemic embolism, mortality and major bleeding,⁶ and apixaban has about 30% renal elimination. Apixaban therapy in this subgroup was more effective than warfarin treatment in reducing stroke, systemic embolism and mortality. The most reassuring finding in patients with renal impairment is the substantial reduction in major bleeding with apixaban therapy as compared to warfarin.

A common question is whether patients who are stable on warfarin should be switched to apixaban. The trial showed consistent reductions in stroke and lower rates of bleeding with apixaban versus warfarin in patients who had and who had not been previously treated with vitamin K antagonists. Moreover, the reductions in stroke and in bleeding were consistent in centers that had excellent INR control as reflected by being in highest quartile of time in therapeutic range among warfarin-treated patients. Thus, the trial data show that the overall benefits in the trial apply to patients previously on warfarin and patients in settings of excellent INR control.

There are a number of important practical issues with the use of apixaban in atrial fibrillation. Patients with "valvular atrial fibrillation" – defined as mechanical prosthetic valves and/or moderate or severe mitral stenosis – should not be treated with apixaban. Apixaban dose should be reduced from 5 mg bid to 2.5 mg bid for patients with two of three "high-risk" criteria: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. Apixaban should not be used for patients with creatinine clearance <25 to 30 ml/min. For patients on warfarin, the INR should drop to <2.0 before initiating apixaban. For invasive procedures with relatively low risk of bleeding, hold apixaban for 2-3 half-lives (1-2 days), and for higher risk of bleeding, 4-5 half-lives (2-3 days). For bleeding, use local measures, blood products, hemodynamic support, and factor replacement with pro-thrombin complex concentrate or activated factor VII has not been studied but might be considered, including with hematology consultation. Oral activated charcoal, if given within two to six hours of apixaban ingestion, will decrease plasma concentrations. Cardioversion while on apixaban appears to be safe, with none of the over 300 patients on apixaban undergoing cardioversion in ARISTOTLE having stroke in the next 30 days. While there are no food and many fewer drug interactions than with warfarin, strong inhibitors of CYP 3A4 and P-glycoprotein inhibitors, like ketoconazole or clarithromycin, will increase drug effect and the 2.5 mg bid dose should be used. While chromogenic Xa assay provides a measure of the effect. However, because aPTT and PT are not closely correlated with drug levels and regular monitoring is not needed, other strategies to measure and to promote adherence should be considered.

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References

1. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
3. Piccini JP, Lopes RD, Mahaffey KW. Oral factor 1 inhibitors for the prevention of stroke in atrial fibrillation. Curr Opin Cardiol 2010;25:312-320.
4. Al-Khatib SM, Alexander JH, Lopes RD, Mahaffey KW, Patel MR, Granger CB. Promise of factor Xa inhibition in atrial fibrillation. Curr Cardiol Rep 2012;14:70-78.
5. Easton JD, Lopes RD, Bahit MC, et al. ARISTOTLE Committees and Investigators. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischarmic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503-511.
6. Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol 2011;57:1339-48.

Keywords: Anticoagulants, Atrial Fibrillation, Body Weight, Double-Blind Method, International Normalized Ratio, Myocardial Infarction, Renal Insufficiency, Stroke

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